A sustained release preparation with controlled release of a drug can maintain the blood concentration of the drug within the therapeutically effective range throughout a considerably long period of time. That is, the sustained release preparation, as compared with usual preparations, is more suitable for improvement of the therapeutic effectiveness by maintaining the effective blood concentration of the drug and also for improvement of patients' QOL (quality of life) by suppression of adverse reactions caused by unnecessary increase or drastic change of the blood concentration and by maintenance of patients' compliance. Thus sustained release preparations have long been studied from various viewpoints.
For example, sustained release oral preparations such as spansules, spantalontabs, repetabs, etc. are known. However preparations with a large diameter such as tablets and capsules may be undesirable for oral administration in the aged, children, or patients with difficulty in swallowing. For easier oral administration of a sustained release preparation to these people, the preparation should desirably be composed of as small as possible units that are still capable of sustained release and be able to be formulated as a suspension, paste, or syrup as needed. Such a sustained release preparation composed of small units is suitable also for easy adjustment of the dose when the necessary dose varies according to the difference in sensitivity, tolerance, progression of diseases, etc.
Microcapsule preparations are known among sustained release preparations having an average particle size of 200 μm or less. For example, a preparation of microcapsules produced by the drying-in-liquid method has been disclosed in Japanese Unexamined Patent Publication No. 109711/1986 etc. Production of microcapsules, as compared with production of particles by layering or coating, is industrially disadvantageous in respect of apparatus, equipments, factors to be controlled, etc. In case of microcapsules containing a water-soluble drug where water or an aqueous solvent is charged in the capsule, problems such as softening of capsules due to miscibility of the water with the coating film during capsulation and/or water migration after capsulation and difficulty in prevention of the influence of water on the content along time-course, are apt to arise. In addition, when the organic solvents are used in the production of the microcapsules, attention should be paid to safety and environmental problems such as residue, inflammability, exhaust gas of the organic solvents.
“Layering” means a technique for formation of granulation product containing a drug, etc. by coating the surface of core particles with the drug alone or in combination with a filler, binder, etc. “Coating” is a technique for formation of a layer consisting of fat or fatty oil, a polymer, etc. on the surface of solid particles such as core particles or granulation product whereby drug-release control, contribution to stability, or masking of unpleasant odor, taste, etc. is attained. Layering methods include granulation by spraying a solution, suspension, or dispersion of the coating ingredients followed by drying, and granulation by addition, adhesion, and binding of the coating ingredients while spraying a binder-containing solution followed by drying. Coating methods include spraying of a solution, suspension, or dispersion of the film components followed by drying.
A persistent severe pain disturbs patients' daily activities due to insomnia, loss of appetite, etc. may cause, in physical conditions, loss of strength, general prostration, and even aggravation of the underlying disease, and in mental conditions, various adverse influences such as fear, anxiety, and apprehension of occurrence of neurological symptoms such as depression. Therefore resolution or alleviation of pain has been the great important problems as well as treatment of the underlying disease.
A number of drugs are now available as analgesic agents, among which morphine, an opioid analgesic agent, is representative. The analgesic effect of morphine is remarkable. Morphine is included in the list of basic drugs of The World Health Organization (WHO) for patients suffering from cancer with persistent severe pain, and WHO recommends oral administration whenever possible, intrarectal administration when oral administration is impossible, injection when intrarectal administration is also impossible, dose adjusted for a patient, regular administration at specified time intervals, efforts to prevent adverse reactions due to the drug as far as possible, consideration of patients' mental state, etc. Morphine, having a short half-life, requires frequent administration; for instance, every 4 hours even while sleeping at night is necessary for persistent efficacy, and this has posed problems in patients' compliance and QOL.
For solving these problems, sustained release preparations of morphine have been developed, including MS CONTIN tablet (trade name by Shionogi & Co. Ltd.) and capsules and sticks of KADIAN (trade name by Faulding Co.) which are prepared by matrix formation with a water-insoluble polymer compound or by film coating. MS Contin tablets are film-coated tablets of about 7.1 mm in diameter and about 4.4 mm in thickness, prepared by coating with a higher alcohol film the granules where morphine sulfate is formed into matrix with a gel-forming polymer compound such as hydroxyethylcellulose. MS Contin tablets are sustained release tablets as the basic unit designed so that morphine in the tablet is released gradually by water that has penetrated through the higher alcohol film into the tablet to maintain the analgesic effect by twice-a-day administration. However, oral administration is difficult in some cases and fine adjustment of the dose is impossible because one tablet is the basic unit of the sustained release. In addition, because the tablets, when broken, lose their sustained releaseability, much morphine may be released at a time when the patient has crunched the tablet in the mouth, so that the blood concentration may be increased rapidly to cause serious adverse reactions such as dyspnea and disturbance of consciousness. KADIAN is a preparation of which units are sustained release pellets (particles) of 1.0 to 1.7 mm in average particle size. These sustained release pellets are filled in hard capsules to prepare KADIAN capsules (No. 2 or No. 4 capsules), or divided and packaged to prepare KADIAN sticks. The mechanism of sustained release of KADIAN is pH-dependent control of release of morphine by the coating of the hybrid type consisting of a water-insoluble polymer compound, an acid-soluble polymer compound, and an enteric polymer compound. However, in patients with decreased digestive function, sustained release of the type that is dependent on the pH in the digestive tract may not be effective enough. Furthermore, there are some additional disadvantages in respect of easiness of administration, such as bulkiness of preparations with high content of morphine, and being unable to be prescribed in the form of a suspension, paste, or syrup by addition of an adequate amount of water, an aqueous solution etc. before administration.
In general, during layering or coating of core particles or granulation products having an average particle size of 300 μm or less, cohesion or scattering of the particles or granulation products is apt to occur, and the specific surface area becomes large, so that it is difficult to obtain stable sustained release preparations when the amount of the coating agent is 50% by weight or less of the amount of the core particles or solid particles. Japanese Unexamined Patent Publication No. 2001-106627 has disclosed sustained release granules having an average particle size of 50 to 250 μm that can be prepared more easily than microcapsules and without use of any organic solvents and can be formulated into fine granules or dry syrup preparations where weight ratio of the water-insoluble polymer compound is 40 to 150% of that of the active ingredient, theophylline. However, as theophylline is slightly soluble in water, the ability of granules to sustain release hardly functions or is markedly decreased when the drug is highly water-soluble. In WO98/10756, a method for coating with a polymer that can sustain release when water is used as the solvent, and a method for coating only with a heat-fused wax were attempted: latex of ethylcellulose, copolymer of ethyl acrylate and metacrylic acid, aminoalkyl methacrylate, etc. have been developed as polymers that can sustain release with an aqueous solvent, but even with these, it is difficult to control release of a highly water-soluble drug over a long time period, and it has been reported that the steady zero-order release of a drug is impossible even with a very thick film for the release controlling.